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Sepsis remains a leading cause of morbidity and mortality worldwide, with outcomes highly influenced by host immune responses. While environmental and pathogen-related factors are well recognized, the contribution of host genomic variants to sepsis susceptibility and severity is increasingly appreciated. Because approximately 85% of known disease-causing mutations reside in the exome, whole exome sequencing (WES) offers a powerful strategy to uncover pathogenic variants in critically ill patients and to identify potential inborn errors of immunity that may modulate disease course. In the present study, we performed WES on 31 sepsis patients across different age groups, stratified into pre-school-aged children, school-aged children, and adults, and identified multiple genes harboring high- or medium-impact variants. Of particular interest, a high-impact TLR8 variant (rs3764880: A>G; p.Met1Val) was observed across all the age groups and predominantly in individuals with bacterial sepsis. Single-cell RNA sequencing of peripheral blood mononuclear cells demonstrated that TLR8 was highly expressed in non-classical monocytes, with transcription levels markedly elevated in carriers of the variant. Functional studies revealed that this TLR8 variant enhanced IFN-β secretion upon ligand stimulation, suggesting that dysregulated TLR8 signaling might modulate host inflammatory responses during bacterial sepsis. Given the established role of IFN-β in exacerbating sepsis severity, these findings support a model in which the TLR8 rs3764880 variant contributes to sepsis pathophysiology by amplifying IFN-β-mediated monocyte responses. This study underscores the importance of integrating genomic and functional immunologic analyses to identify host determinants of sepsis, highlights TLR8 as a potential biomarker and therapeutic target, and provides a framework for precision medicine approaches to predict and modulate outcomes in bacterial sepsis.